19-55147008-C-T

Position:

chr19-55147008-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003283.6(TNNT1):c.46G>A(p.Glu16Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,609,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TNNT1
NM_003283.6 missense, splice_region

Scores

Splicing: ADA: 0.9913

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.406

Variant links:

Genes affected

TNNT1 (HGNC:11948): (troponin T1, slow skeletal type) This gene encodes a protein that is a subunit of troponin, which is a regulatory complex located on the thin filament of the sarcomere. This complex regulates striated muscle contraction in response to fluctuations in intracellular calcium concentration. This complex is composed of three subunits: troponin C, which binds calcium, troponin T, which binds tropomyosin, and troponin I, which is an inhibitory subunit. This protein is the slow skeletal troponin T subunit. Mutations in this gene cause nemaline myopathy type 5, also known as Amish nemaline myopathy, a neuromuscular disorder characterized by muscle weakness and rod-shaped, or nemaline, inclusions in skeletal muscle fibers which affects infants, resulting in death due to respiratory insufficiency, usually in the second year. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

TNNT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT1	NM_003283.6 link	c.46G>A	p.Glu16Lys	missense_variant, splice_region_variant	3/14	ENST00000588981.6	NP_003274.3	P13805-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT1	ENST00000588981.6 link	c.46G>A	p.Glu16Lys	missense_variant, splice_region_variant	3/14	1	NM_003283.6	ENSP00000467176.1		P13805-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000331

AC:

AN:

241948

Hom.:

AF XY:

0.0000306

AC XY:

AN XY:

130630

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000442

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1457760

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724670

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Nemaline myopathy 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 20, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 16 of the TNNT1 protein (p.Glu16Lys). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. This variant is present in population databases (rs533504444, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with TNNT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1483566). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

.;.;.;T;.;.;T

Eigen

Benign

-0.026

Eigen_PC

Benign

-0.091

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.82

.;T;T;T;T;T;T

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.26

T;T;T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

M;M;M;M;.;.;.

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-2.3

.;N;N;.;.;.;.

REVEL

Uncertain

0.51

Sift

Benign

0.041

.;D;D;.;.;.;.

Sift4G

Benign

0.069

T;T;D;T;.;D;T

Polyphen

0.59

P;P;P;P;.;.;.

Vest4

0.20

MutPred

0.19

Gain of methylation at E16 (P = 0.0062);Gain of methylation at E16 (P = 0.0062);Gain of methylation at E16 (P = 0.0062);Gain of methylation at E16 (P = 0.0062);Gain of methylation at E16 (P = 0.0062);Gain of methylation at E16 (P = 0.0062);Gain of methylation at E16 (P = 0.0062);

MVP

0.92

MPC

0.64

ClinPred

0.11

GERP RS

2.1

Varity_R

0.23

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.81

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over